Dopamine D4 receptor is one of G protein-coupled receptors (GPCRs), and is highly expressed in frontal association area associated with attention behavior and cognitive function. Hence, a dopamine D4 receptor agonist is expected to be used for treating a central nervous system disease related to higher brain function such as attention deficit hyperactivity disorder (ADHD). ADHD is one of developmental disorders accompanying inattention, hyperactivity, and impulsivity as predominant symptoms, which appear in childhood. Also, it is known that the predominant symptoms of ADHD persist into adulthood. As a first-choice drug for treating ADHD, methylphenidate which is one of central nervous system stimulants has been used. Methylphenidate exhibits a fast-acting therapeutic effect, which is thought to be produced by the regulation of dopamine transporter function associated with the release of dopamine that is a neurotransmitter. However, methylphenidate is at risk for drug dependence or drug abuse, and also at risk for cardiovascular side effects such as palpitation, tachycardia, and blood-pressure variation. Thus, as a medicament for treating ADHD which is at low risk for drug dependence, a selective noradrenaline reuptake inhibitor, atomoxetine which is one of non-central nervous system stimulants has been used. However, atomoxetine requires an adequate period after the administration to exert its therapeutic effect. Accordingly, it has been desired to develop a medicament for treating ADHD, which has a reduced risk for drug dependence and also a reduced risk for cardiovascular side effects, and exhibits a fast-acting therapeutic effect.
Recently, it has been reported that ADHD patients have mutations in dopamine transporter genes or dopamine D4 receptor genes (e.g. Non-Patent Reference 1). Also, it has been reported that children with gene polymorphism in a seven times repeating sequence of 48 bp within the third exon of dopamine D4 receptor genes have the delayed development of cerebral cortex (e.g. Non-Patent Reference 3). In addition, it has been reported that dopamine D4 receptors are highly expressed in frontal association area associated with attention behavior and cognitive function (e.g. Non-Patent Reference 2). Hence, it has been thought that dopamine D4 receptors are associated with attention and cognitive functions. In addition, it is well known that dopamine D4 receptors are not expressed in nucleus accumbens associated with drug dependence.
Accordingly, a drug which exhibits a selective dopamine D4 receptor agonistic effect has been expected as a medicament for treating a central nervous system disease related to dopaminergic nerves, especially a medicament for treating ADHD which exhibits a fast-acting therapeutic effect with reduced side effects such as drug dependence.
Patent Reference 1 discloses a dopamine D4 receptor ligand of formula I:
wherein
R1 and R2 each individually signify lower-alkyl or amino;
A is

B signifies hydrogen in A4, A5 and A6;
in A1-A6;lower-alkoxy in A4-A6; andlower-alkyl, styryl, phenylethynyl, or benzoyloxy-lower-alkyl in A1 and A2;
n signifies 0-2;
m, p signify 0, 1; and
R3, R4, R5 and R6 each independently signify hydrogen, halogen, lower-alkyl, trifluoromethyl, lower-alkoxy or nitro. Patent Reference 1 also discloses that such compound is useful for the regulation or prophylaxis of a disease caused by disturbance in the dopamine system (e.g. psychosis such as schizophrenia).
Said compound does not encompass compounds wherein B is a heteroaryl ring-containing substituent. Thus, the present compound is different from the compound of Patent Reference 1 in each chemical structure.